Stable Pharmaceutical Compositions and Methods of Making and Using Same

ABSTRACT

Stable compositions comprising ketotifen or a ketotifen salt and methods of preparing such compositions are provided. The pH of the compositions remains at less than about 5 during storage. The methods comprise preparing pharmaceutical compositions comprising ketotifen or a ketotifen salt, and adjusting their pH to less than 5, thus slowing the changes of the active ingredients.

This application is a continuation-in-part of U.S. application Ser. No.11/257,196, filed Oct. 24, 2005, which is a continuation-in-part of U.S.application Ser. No. 10/972,571 filed Oct. 25, 2004, and which claimsthe benefit of U.S. Provisional Application No. 60/623,758, filed Oct.29, 2004, the entire contents of these applications are herebyincorporated herein by reference.

BACKGROUND

The present invention generally relates to stable pharmaceuticalcompositions and methods of making and using such compositions. Inparticular, the present invention relates to stable ophthalmiccompositions containing antihistamines or mast cell stabilizers, andmethods of making and using the same.

Ophthalmic compositions are useful for the treatment and temporaryprevention of the signs and symptoms of ocular conditions, includingallergic conjunctivitis, itching of the eye and redness of the eye.Methods of treating ocular conditions include administering to a humansubject suffering therefrom or susceptible thereto an ophthalmiccomposition, for example, in the form of eye drops.

Ophthalmic compositions may also be useful for the treatment of dry eyecondition, including inflammatory dry eye condition. Ophthalmiccompositions may be formulated as single or multi dose units, with orwithout the use of a preservative, and may be manufactured by mixingvarious ingredients. The compositions may be packaged in single ormultiple dosage forms, such as closed bottles, tubes, or othercontainers made from materials such as glass or plastic. In some cases,the packaging for the ophthalmic composition may be free orsubstantially free of antioxidant (e.g., as used in compositionsdescribed in U.S. Pat. Nos. 6,455,547 and 6,576,649).

Typically, the compositions are administered as drops, with one or moredrops of the composition being applied to an eye of the subjectsuffering from or susceptible to ocular conditions one or more times perday, although the frequency of administration of such compositions maybe dependent on multiple factors, including the makeup of the particularcomposition and the condition for which the compositions are used.

Ophthalmic solutions may contain buffers, various surfactants,stabilizers, isotonic agents and the like which aid in making theophthalmic compositions more comfortable to the user. Oftentimes theophthalmic solutions contain such agents and the like to maintain apredictable level of efficacy over a predetermined or expected lifetime.

Maintenance of efficacy and stability of ophthalmic solutions may berequired to meet various federal health and safety regulations, e.g.,shelf life testing, sterility, etc. For example, ophthalmic solutionsmay be required to contain expiration dates posted on their container,which may be predicated on the stability of the active ingredients andother conditions inherent in the formulation and environmental exposuresof the product. Oftentimes stabilizing agents, although effective inmaintaining specific properties of the formulation, are undesirableingredients as they may cause adverse side effects in end-users orpromote the degradation of active agents in the formulation.

Of particular importance for efficacy and commercialization ofophthalmic solutions is solution stability. Solution stability may bedependent on the interactions of all compounds present in theformulation as well as temperature and pH. Ophthalmic compositionstypically have a pH anywhere from 4 to 6. The pH value is generallytargeted to provide a specific level or range which provides the leastamount of discomfort to the end user. Conventionally, a buffer (e.g.,buffers including citrates, phosphates, borates, bicarbonates, sodiumsalts, potassium salts, etc. or a buffer with intrinsic antimicrobialproperties such as a sodium borate/boric acid buffer) is used to achieveand maintain a desired pH of the compositions, and/or an acid or base isadded to adjust the pH of the compositions to the desired level.However, certain otherwise pharmaceutically effective active agents mayundergo degradation when formulated in the presence of buffering agents.

Furthermore, it may be desirable for an ophthalmic composition toinclude a plurality of active agents. In such situations, it may bedifficult or uneconomical to meet a particular shelf life target orfederal regulatory requirements due to some instability of thecombination of the active agents or other interaction, e.g., withcertain buffering agents. This may be the result of some chemicalreactivity or incompatibility of the compounds or salts thereof, forexample, which leads to degradation of one or more of the active agents.Such degradation shortens the shelf life of the solution and may renderthe formulation pharmaceutically ineffective or non-compliant withfederal regulatory requirements.

It is therefore desirable to formulate active agents in an ophthalmiccomposition wherein the efficacy of the active agents is maintained foran extended period of time. In addition, it is also desirable to providesuch composition, the target specifications of the active agents ofwhich are maintained for an extended period of time.

SUMMARY

In general, the present invention provides pharmaceutical compositionscomprising at least an active ingredient, wherein the compositions havea low initial pH and the stability of said at least an active ingredientin the compositions is maintained for an extended period of time.

The present applicants unexpectedly have discovered that a compositionof one or more active agents may be formulated at a relatively lowinitial pH, the active agents thereafter having exceptionally goodstability in such composition.

In one aspect, the composition comprises at least an ophthalmic activeagent or ingredient.

In another aspect, the composition is a topical composition.

In still another aspect, the active agent or ingredient comprisesketotifen or a salt thereof.

In yet another aspect, the composition comprises: (a) ketotifen or asalt thereof; and (b) naphazoline or a salt thereof.

In a further aspect, the present invention provides a method ofpreparing a stabilized pharmaceutical composition, wherein the stabilityof at least an active ingredient of the composition is maintained for anextended period of time. The method comprises: (a) admixing a pluralityof materials comprising said at least an active ingredient and a carrierto form a mixture; and (b) adjusting a pH of said mixture to less thanor equal to 5 with a pH adjusting material, thereby producing thecomposition having said stability.

In still another aspect, the composition comprising: (a) ketotifen or asalt thereof in a concentration of from about 0.001% to about 0.2%(weight/volume or “w/v”); (b) naphazoline or a salt thereof in aconcentration of from about 0.001% to about 0.2% (w/v); and (c) water.

In yet another aspect, the plurality of materials further comprises atonicity adjusting agent.

In a further aspect, the plurality of materials further comprises abuffering agent that is capable of maintaining the pH of the compositionat less than or equal to about 5.

In a still another aspect, the method comprises adjusting the pH of thecomposition to a value between about 4.3 and 4.8.

In a further aspect, the method produces said composition, the pH ofwhich is maintainable between about 4.3 to about 4.8 when saidcomposition is kept at 40° C. and 20% relative humidity (“RH”) for atleast 10 days.

In one embodiment, a method of preparing a stabilized ophthalmiccomposition is provided. The method comprises: (a) preparing a mixturecomprising (1) ketotifen or a salt thereof in a concentration from about0.001% to about 0.2%; (2) naphazoline or a salt thereof in aconcentration from about 0.001% to about 0.2%; (3) glycerol in aconcentration from about 2% to 6%; and (4) water; and (b) adjusting a pHof the ophthalmic composition to a value in a range from about 4.3 toabout 4.8 to provide said stabilized ophthalmic composition, whereinsaid pH of the ophthalmic composition is maintained in said range at 40°C. and 20% RH for at least 10 days.

In yet another embodiment, a method of preparing a stabilized aqueousketotifen composition is provided. The method comprises admixing anaqueous composition comprising ketotifen or a salt thereof, with a pHadjusting agent to produce a mixture having a pH between 4.8 and 5,wherein the mixture is essentially free of buffering agents. The methodfurther comprises allowing the pH of the mixture to adjust to between4.3 and 4.8; thereby providing said stabilized aqueous ketotifencomposition such that no more than about 10% of said ketotifen isdegraded at 40° C. and 20% RH for at least 10 days.

DETAILED DESCRIPTION

As used herein, unless otherwise specified, the concentration of acomponent or ingredient of a composition is represented by mass of thecomponent or ingredient per total volume of the composition (i.e.,g/mL), and is typically expressed as a percentage. For example, aconcentration of 1% means 1 g per 100 mL of the composition.

In general, the present invention provides pharmaceutical compositionseach comprising at least an active ingredient, wherein the compositionshave a low initial pH and the stability of said at least an activeingredient in the compositions is maintained for an extended period oftime.

In one aspect, the composition comprises at least an ophthalmic activeagent or ingredient.

In another aspect, the composition is a topical composition.

In still another aspect, the active agent or ingredient comprisesketotifen or a salt thereof.

In yet another aspect, the composition comprises: (a) ketotifen or asalt thereof; and (b) naphazoline or a salt thereof.

In a further aspect, the present invention provides a method ofpreparing a stabilized pharmaceutical composition, wherein the stabilityof at least an active ingredient of the composition is maintained for anextended period of time. The method comprises: (a) admixing a pluralityof materials comprising said at least an active ingredient and a carrierto form a mixture; and (b) adjusting a pH of said mixture to less thanor equal to 5 with a pH adjusting material, thereby producing thecomposition having said stability.

In one embodiment, the stability of at least an active ingredient of thecomposition is maintained for at least 10 days after the manufacture ofsuch composition. In another embodiment, such an extended period of timeis at least one month. In still another embodiment, such an extendedperiod of time is at least two, three, four, five, six, or twelvemonths, or longer.

In still another embodiment, the stability of the active ingredient ismaintained when less than about 20% (or alternatively, in someembodiments with other active ingredients, less than 15%, or less than10%, or less than 5%) (by weight) of the active ingredient has degradedor changed in such period of time.

In one aspect, a composition of the present invention is an aqueoussolution.

In another aspect, a composition of the present invention is anoil-in-water emulsion.

In still another aspect, a composition of the present invention isadministrable to an eye as a drop and becomes more viscous aftercontacting an ocular environment.

In yet another aspect, a composition of the present invention is a gel.

In a further aspect, the present invention provides a method ofstabilizing an ophthalmic composition. The method comprises: (a)preparing a solution of at least an ophthalmic active agent and water;and (b) adjusting a pH of the ophthalmic composition to a value of 5 orlower. In one embodiment, the method provides for solution stability. Inanother embodiment, the method provides an ophthalmic composition thatcan provide comfort to a user of the composition.

As used herein, the term “active agent” or “active ingredient” refers toa compound or composition of matter that when administered to a subject(human or animal) causes a desired pharmacologic and/or physiologiceffect by local and/or systemic action. Ketotifen, a ketotifen salt,naphazoline, and a naphazoline salt are non-limiting examples of activeagents that can be used to formulate ophthalmic compositions of thepresent invention.

As used herein, the term “break point concentration” is definedgenerally as the concentration of a buffering agent that is insufficientto maintain the pH of a solution comprising one or more active agents ata temperature for a given time duration. By way of example, the breakpoint concentration of a citrate buffer for a ketotifen salt solution isthe concentration of citrate that allows a decrease in the pH value ofthe aqueous solution when kept at 40° C. and 20% RH for at least 10days.

As used herein, the phrase “free or substantially free of buffer agent”refers to a composition absent a buffering agent or a composition wherethe amount of buffering agent is less than the break point concentrationof the buffer.

The pH of an aqueous ophthalmic composition comprising an active agent,alone or in combination with other ingredients may be controlled whenformulated with a buffer. However, merely achieving a stable pH of anophthalmic composition comprising an active agent, at a predeterminedvalue, may not be sufficient to maintain the stability of the activeingredient and/or ocular comfort of the ophthalmic composition. Forexample, ketotifen fumarate may degrade upon storage when certainbuffering agents are used. What is desirable is to provide an ophthalmiccomposition the pH of which does not exceed about 5 upon storage. Inparticular, when certain aqueous ophthalmic composition comprisingketotifen or ketotifen salts as active agent are prepared with initialpH values above 5 and stored for any appreciable amount of time, thereoccurs a rapid degradation of the ketotifen, a pH drift and/or increasedocular discomfort. For example, a ketotifen formulation may bemanufactured at an initial pH of 5.5, with an osmolality of about 470mOsm/kg, yet, such a formulation may substantially chemically degradeand drift to a lower pH, which may cause, among other things,unacceptable ocular irritancy in a user. Moreover, adding a buffer tothe aforementioned formulation to stabilize the pH of the formulationmay provide pH stability but may not provide a chemically stablesolution. More likely, the presence of buffer agents may actuallyexacerbate the degradation and ocular discomfort of the formulation.

Buffered aqueous ophthalmic compositions comprising ketotifen or a saltthereof, initially formulated with pH values of greater than 5,maintained their starting pH values but degraded rapidly, e.g., 85% ofthe ketotifen in the solution initially formulated at pH 6.5 degradedafter one week at 55° C./20% RH. In contrast, the pH of unbufferedketotifen solutions with equivalent initial pH values drifted to a lowerpH value over time, in some cases, to less than 4.5, and such solutionsmaintained their chemical stability to a greater extent than thebuffered solutions. Generally, buffered ketotifen solutions with initialpH values of 6.5, 6, 5.5, or 5 resulted in ketotifen degradation farexceeding 10% of the initial amount present in the solution, whereassolutions with initial pH values of less than about 5 without bufferresulted in ketotifen degradation less than 10%.

In view of the tendency of buffered solutions to promote the degradationof active agents such as ketotifen, experiments were conducted todetermine whether low pH solutions of active agents could be stabilizedwith reduced levels of buffering agents. Experiments were conducted todetermine first a break point buffer concentration for ketotifensolutions.

Thus, formulations with lower initial pH values or an amount of bufferbelow the break point buffer concentration were prepared anddemonstrated that such formulations could provide aqueous ketotifenstability for ophthalmic compositions. On the other hand, it wasrecognized that lower pH values would need to be balanced with ocularcomfort. Hence, formulations having an initial low pH value and/or withlower buffer concentrations were prepared and tested for drug stability,pH stability, and ocular comfort and found to satisfy both solutionstability and ocular comfort. These results were generally found to beindependent of additional components in the ketotifen formulation, e.g.,anti-redness agents, vasoconstrictors, decongestants,viscosity-adjusting agents, tonicity-adjusting agents, and/orpreservatives.

Additional experiments were conducted to determine the pH drift andketotifen degradation as a function of initial pH, buffer agent, andconcentration of buffer in ophthalmic compositions. Based onexperimental data, the greatest ketotifen stability was achieved inunbuffered formulations followed by solutions having bufferconcentrations below the break point concentration. From these data, itwas observed that the starting point of the pH significantly affects thestability of the ketotifen in the composition.

Ketotifen or any ophthalmically acceptable ketotifen salt may be used inthe method herein described, although ketotifen fumarate is preferred.Ketotifen fumarate is represented by the following formula:

Ketotifen or a ketotifen salt may be present in a composition producedby a method in a concentration from about 0.001% to about 0.2% (oralternatively, from about 0.001% to about 0.1%). In one embodiment,ketotifen or a ketotifen salt is present in a concentration from about0.01% to about 0.05%; preferably, from about 0.01% to about 0.04%; morepreferably, from about 0.02% to about 0.03%. In some embodiments, themethod provides stability to compositions comprising a ketotifen orketotifen salt in a concentration such that the concentration ofketotifen in the composition is from about 0.01% to about 0.05%;preferably, from about 0.0225% to about 0.0275%; more preferably, about0.025%. Concentrations of ketotifen salts yielding such concentrationsof ketotifen may be readily calculated; for example, using ketotifenfumarate in a concentration of about 0.0345% in the composition providesa concentration of ketotifen in the composition of 0.025%.

The ophthalmic compositions prepared by the methods herein disclosed mayinclude an anti-redness agent, which may relieve redness in the eye. Thepreferred anti-redness agent is naphazoline or an ophthalmicallyacceptable salt thereof such as, for example, naphazoline hydrochloride.Other anti-redness agents that may be used include, but are not limitedto, tetrahydrozoline, ephedrine, phenylephrine, oxymetazoline,xylometazoline, pseudoephedrine, tramazoline, other vasoconstrictors,combinations thereof, as well as ophthalmically acceptable salts thereof(e.g., tetrahydrozoline hydrochloride).

Naphazoline hydrochloride is represented by the following formula:

Naphazoline or a naphazoline salt may be present in a compositionproduced a method of the present invention in a concentration from about0.001% to about 0.2% (or alternatively, from about 0.001% to about0.1%). In one embodiment, naphazoline or a naphazoline salt is presentin a composition at a concentration from about 0.01% to about 0.1%;preferably, from about 0.01% to about 0.07%; more preferably, from about0.02% to about 0.06%. In some embodiments, the method provides stabilityto compositions comprising naphazoline or a naphazoline salt in aconcentration such that the concentration of naphazoline in thecomposition is about 0.02% to about 0.05%. Concentrations of anaphazoline salt yielding such concentrations of naphazoline base may bereadily calculated; for example, using naphazoline hydrochloride in aconcentration of about 0.025% in the composition provides aconcentration of naphazoline base in the composition of 0.021%.

In one aspect, the method herein described provides stability topharmaceutical compositions, such as ophthalmic solutions, adjusted withtonicity agents to approximate the osmotic pressure of normal lachrymalfluids, which, as stated in U.S. Pat. No. 6,274,626, is equivalent to a2.5% solution of glycerol. Osmotic pressure, measured as osmolality, isgenerally about 225 to 400 mOsm/kg for conventional ophthalmicsolutions.

However, in some embodiments, the pharmaceutical composition may beformulated to osmolality in the range from about 400 to about 875mOsm/kg, for some desired purposes. In particular, such osmolality maybe employed if the composition is formulated to be well tolerated by auser. For example, co-assigned U.S. Patent Application No. 2006/0148899,incorporated herein by reference in its entirety, provides forophthalmic solutions having osmolality from 400 to 875 mOsm/kg, whichhave been found still to provide comfort to a user.

The nonionic tonicity agent is preferably glycerol, although othernonionic tonicity agents may be used such as, for example, urea,sorbitol, mannitol, propylene glycol, and dextrose. In otherembodiments, glycerol is used as the nonionic tonicity agent in aconcentration of from 2% to 6%, preferably from 3% to 5%, morepreferably about 4% such that the composition has an osmolality fromabout 200 to about 700 mOsm/kg, preferably from about 400 to about 600mOsm/kg.

The ophthalmic compositions of the method comprising ketotifen or aketotifen salt, an anti-redness agent, a nonionic tonicity agent, andwater, may optionally include a preservative. The ophthalmiccompositions may optionally include a buffer agent to maintain the pH ofthe composition. In a preferred embodiment, the ophthalmic compositionis free or substantially free of buffer agents that would have beenroutinely used to achieve and/or maintain the pH of pharmaceuticalcompositions.

In certain embodiments, an ophthalmic composition of the presentinvention further comprises a carboxy-containing vinyl polymer. In oneembodiment, such a polymer comprises a lightly crosslinkedcarboxy-containing vinyl polymer.

Crosslinked carboxy-containing polymers used in practicing thisinvention are, in general, well known in the art. In one embodiment,such polymers may be prepared from at least about 90% (by weight) and,preferably, from about 95% to about 99.9% (by weight), based on thetotal weight of monomers present, of one or more carboxy-containingmonoethylenically unsaturated monomers. Acrylic acid is the preferredcarboxy-containing monoethylenically unsaturated monomer, but otherunsaturated, polymerizable carboxy-containing monomers, such asmethacrylic acid, ethacrylic acid, β-methylacrylic acid (crotonic acid),cis-α-methylcrotonic acid (angelic acid), trans-α-methylcrotonic acid(tiglic acid), α-butylcrotonic acid, α-phenylacrylic acid,α-benzylacrylic acid, α-cyclohexylacrylic acid, β-phenylacrylic acid(cinnamic acid), coumaric acid (o-hydroxycinnamic acid), umbellic acid(p-hydroxycoumaric acid), and the like can be used in addition to orinstead of acrylic acid.

Such polymers may be crosslinked by a polyfunctional crosslinking agent,preferably a difunctional crosslinking agent. The amount of crosslinkingshould be sufficient to form insoluble polymer particles, but not sogreat as to unduly interfere with sustained release of the medicament.Typically, the polymers are only lightly crosslinked. Preferably, thecrosslinking agent is contained in an amount of from about 0.01% toabout 5% (by weight); more preferably, from about 0.1% to about 5% (byweight), and more preferably from about 0.2% to about 1% (by weight),based on the total weight of monomers present. Included among suchcrosslinking agents are non-polyalkenyl polyether difunctionalcrosslinking monomers such as divinyl glycol;2,3-dihydroxyhexa-1,5-diene; 2,5-dimethyl-1,5-hexadiene; divinylbenzene;N,N-diallylacrylamide; N,N-diallymethacrylamide and the like. Alsoincluded are polyalkenyl polyether crosslinking agents containing two ormore alkenyl ether groupings per molecule, preferably alkenyl ethergroupings containing terminal CH₂═C< groups, prepared by etherifying apolyhydric alcohol containing at least four carbon atoms and at leastthree hydroxyl groups with an alkenyl halide such as allyl bromide orthe like, e.g., polyallyl sucrose, polyallyl pentaerythritol, or thelike; see, e.g., U.S. Pat. No. 2,798,053. Diolefinic non-hydrophilicmacromeric crosslinking agents having molecular weights of from about400 to about 8,000, such as insoluble di- and polyacrylates andmethacrylates of diols and polyols, diisocyanate-hydroxyalkyl acrylateor methacrylate reaction products of isocyanate terminated prepolymersderived from polyester diols, polyether diols or polysiloxane diols withhydroxyalkylmethacrylates, and the like, can also be used as thecrosslinking agents; see, e.g., U.S. Pat. Nos. 4,192,827 and 4,136,250.

The crosslinked polymers may be made from a carboxy-containing monomeror monomers as the sole monoethylenically unsaturated monomer present,together with a crosslinking agent or agents. Preferably, the polymersare ones in which up to about 40%; and more preferably, from about0.0001% to about 20% by weight, of the carboxy-containingmonoethylenically unsaturated monomer or monomers has been replaced byone or more non-carboxyl-containing monoethylenically unsaturatedmonomer or monomers containing only physiologically andopthalmologically innocuous substituents, including acrylic andmethacrylic acid esters such as methyl methacrylate, ethyl acrylate,butyl acrylate, 2-ethylhexylacrylate, octyl methacrylate,2-hydroxyethyl-methacrylate, 3-hydroxypropylacrylate, and the like,vinyl acetate, N-vinylpyrrolidone, and the like; see U.S. Pat. No.4,548,990 for a more extensive listing of such additionalmonoethylenically unsaturated monomers. Particularly preferred polymersare lightly crosslinked acrylic acid polymers wherein the crosslinkingmonomer is 2,3-dihydroxyhexa-1,5-diene or 2,3-dimethylhexa-1,5-diene.Preferred commercially available polymers include polycarbophil (NoveonAA-1) and Carbopol®.

The crosslinked polymers used in practicing this invention arepreferably prepared by suspension or emulsion polymerizing the monomers,using conventional free radical polymerization catalysts, to a dryparticle size of not more than about 50 μm in equivalent sphericaldiameter; e.g., to provide dry polymer particles ranging in size fromabout 1 to about 30 μm, and preferably from about 3 to about 20 μm, inequivalent spherical diameter. Using polymer particles that wereobtained by mechanically milling larger polymer particles to this sizeis preferably avoided. In general, such polymers will have a molecularweight which has been variously reported as being from about 250,000 toabout 4,000,000, and from 3,000,000,000 to 4,000,000,000.

In a preferred embodiment of the invention, the particles of crosslinkedpolymer are monodisperse, meaning that they have a particle sizedistribution such that at least 80% of the particles fall within a 10 μmband of major particle size distribution. More preferably, at least 90%and most preferably at least 95%, of the particles fall within a 10 μmband of major particle size distribution. Also, a monodisperse particlesize means that there is no more than 20%, preferably no more than 10%,and most preferably no more than 5% particles of a size below 1 μm. Theuse of a monodispersion of particles will give maximum viscosity and anincreased eye residence time of the ophthalmic medicament deliverysystem for a given particle size. Monodisperse particles having aparticle size of 30 μm and below are most preferred. Good particlepacking is aided by a narrow particle size distribution.

In one embodiment, the ophthalmic composition comprises a polymercomponent that consists essentially of one or more of theabove-described crosslinked carboxy-containing polymers. This means thatno additional polymers are present in the composition that wouldsignificantly affect the medicament release profile. Polymers andoligomers used as excipients, carriers, demulcents, or othernon-medicament-interactive functions are still included within thecomposition so long as the medicament release profile is notsignificantly altered. However, in this embodiment no polymer particles(water insoluble polymers) which materially affect release e.g., acationic exchange resin) are present in addition to the crosslinkedcarboxy-containing polymers, and typically no other polymers (soluble orinsoluble) of any kind are present in the composition.

When such crosslinked carboxy-containing polymer is present in anophthalmic composition of the present invention, it is generally presentin an amount ranging from 0.5 to 2%; preferably, from about 0.5% toabout 1.2% (w/v); and more preferably, from about 0.6 to about 0.9%(w/v).

The ophthalmic compositions may include an acid or base to adjust the pHof the composition. The method is useful for the stabilization ofophthalmic solutions that have a pH value initially adjusted such thatthe pH value of the ophthalmic composition thereafter is maintainablebetween about 4.3 and about 4.8 at least for 10 days at 40° C. and 20%relative humidity. The solutions may be adjusted to any pH value suchthat the pH value of the ophthalmic composition thereafter is betweenabout 4.3 and about 4.8. The solutions preferably may be initiallyadjusted to have a pH value above 4.5 or below 5.0. Preferably, theadjusted pH value is higher than the thereafter pH value of thecomposition. Most preferred is an initially adjusted solution having apH value of about 4.8.

Typically, only small amounts of an acid or base will be needed toadjust the initial pH of the solution. By way of example, an acid andbase suitable for adjusting the pH are hydrochloric acid and sodiumhydroxide. Fumaric acid or fumaric acid/sodium fumarate may also besuitable to adjust the pH of the solution. A buffering agent (e.g.,buffers including citrates, phosphates, borates, bicarbonates, sodiumsalts, potassium salts, etc.; or a buffer with intrinsic antimicrobialproperties such as a sodium borate/boric acid buffer) may be usedprovided that the breakpoint buffer concentration is not exceeded. If abuffering agent is used, it is further preferred that no more than 10%of the concentration of any active agents in the composition isdegraded, for example, at 40° C. and 20% RH for at least 10 days.Preferably, the ophthalmic solution is free or substantially free ofbuffering agent.

In one embodiment, the method is useful for the stabilization ofcompositions that include a preservative. In another embodiment, themethod is useful for the stabilization of compositions that does notinclude a preservative. A preservative is preferred when the compositionis packaged for multidose units, but may be absent from the compositionif desired (e.g., in single dose units of the composition). Anypreservative may be used with the compositions. Preservatives that maybe used include Polyquad preservative (Alcon); perborate (e.g., sodiumperborate from Ciba); Purite preservative (stabilized chlorine dioxide)(Allergan); other quaternary ammonium compounds such as benzalkoniumchloride; alkyl-mercury salts of thiosalicylic acid such as, forexample, thiomersal, phenylmercuric nitrate, phenylmercuric acetate, andphenylmercuric borate; parabens such as, for example, methylparaben orpropylparaben; alcohols such as, for example, chlorobutanol, benzylalcohol, and phenyl ethanol; guanidine derivatives such as, for example,chlorhexidine or polyhexamethylene biguamide; and the like. When apreservative is used in the composition, the preservative is typicallyprovided in a concentration of about 0.005% to 0.02%, preferably 0.01%,although other concentrations may be used.

In one embodiment, the method herein described provides for preparing astabilized ophthalmic composition. The method comprises the steps ofpreparing an aqueous solution consisting essentially of ketotifen or aketotifen salt in a concentration of from about 0.01% to about 0.05%;naphazoline or a naphazoline salt in a concentration of from about 0.01%to about 0.1%; glycerol; benzalkonium chloride; and water. In oneembodiment, the aqueous solution aqueous solution consists essentiallyof ketotifen or a ketotifen salt in a concentration of from about 0.01%to about 0.05%; naphazoline or a naphazoline salt in a concentration offrom about 0.01% to about 0.1%; glycerol; benzalkonium chloride; water;and a buffering agent. The method provides for adjusting the pH value ofthe aqueous solution to less than or equal to about 5 by adding a pHadjusting agent, and providing a stabilized ophthalmic composition wherethe pH value of the ophthalmic composition is maintainable between about4.3 to about 4.8 when kept at 40° C. and 20% RH for at least 10 days.

As used herein, “maintainable” and grammatical equivalents thereofrefers generally to a value of a property of a composition that iscapable of being determined, that stays within a defined range or meetsa specified target value during an interval of time associated with thestorage of the composition. By way of example, an ophthalmic compositionstored at 40° C. and 20% RH for at least 10 days that is determined tohave a value corresponding to a defined range or specified target value,that value would be “maintainable.” An example of values that may bemaintainable in accordance with the method herein described includes,without limitation, pH, ocular comfort and concentrations of the portionof an active agent that has not degraded or changed.

Concentrations of one or more active agents may change during storage.As used herein, “during storage” refers to any interval of timeassociated with the preparation, handling, sterilizing, transporting anddistributing or marketing of the composition. The composition may be inwhatever container or form as may be desirable. During storage alsoincludes accelerated aging testing, or other testing as may be requiredby state and federal regulation, e.g., Food and Drug Administration(FDA) rules, regulations and protocols. By way of example, duringstorage includes 40° C. and 20% relative humidity for at least 10 days.

If the amount of active agent falls below a predetermined level thecomposition may not provide the desired pharmaceutical effect that wasintended. Furthermore, a shelf life of an ophthalmic composition may becorrelated to or predicted by the amount of initial concentration ofactive agent(s) remaining at any given interval of time afterformulating, packaging, sterilizing, etc. In one embodiment of a methodof stabilizing an ophthalmic composition, a ratio of a determinedconcentration of an active agent in the composition after an interval oftime from when the composition is formulated to an initial concentrationof the active agent in the composition is provided. Generally the ratiomay be expressed in percentage that has degraded. For example, an activeagent with an initial concentration of 10 μg/L that degrades, forexample, during storage to 8 μg/L of active agent would have 20% of theactive agent degraded. Concentration of an active agent in a compositionmay be determined by a HPLC method. The initial concentration maycorrespond to a stated concentration of active agent on a label affixedto the container, box or insert provided with the ophthalmiccomposition, e.g, “label claim,” or to a pharmaceutically effectiveconcentration of active agent.

Degradation of active agent refers generally to an active agent that haschanged chemically such that a pharmaceutical property of the activeagent is reduced or eliminated. Methods of determining the amount ofdegradation of active agents and concentrations of initial active agentremaining after an interval of time has elapsed are generally known. Forexample, an active agent that is detectable by a detection methodgenerally used to determine a concentration of the active agent may beused to determine whether the concentration of the active agent hasdecreased relative to its initial formulated concentration. Thedetection method may only measure the concentration of activeingredient.

By adjusting the pH value of an ophthalmic solution such that the pHvalue of the ophthalmic composition is maintainable between about 4.3and about 4.8 for example, at 40° C. and 20% RH for at least 10 days, itmay be possible to substantially eliminate the need for a buffer agent,or it may provide for the use of very low concentrations of bufferingagents. Providing ophthalmic compositions free or essentially free ofbuffer improves ocular comfort of the composition for the user. Themethod herein described may be useful for providing acceptable ocularcomfort ophthalmic compositions comprising ketotifen as well ascompositions comprising ketotifen in combination with anti-rednessagents, for example, naphazoline or naphazoline salts.

As used herein, ocular comfort refers to an effect of an ophthalmiccomposition on a user upon contact of the composition with an ocularspace of the user. Ocular comfort is determined by a user responding tothe introduction of drops of a composition into the eye of the user. Byway of example, the response may be graded on a numerical scale, from 1to 10, 1 representing mostly discomfort, and 10 representing mostlycomfort or the response may be an indication that the ocular comfort isacceptable or unacceptable.

In certain embodiments, the methods herein disclosed can be useful forthe stabilization of compositions that are also free or substantiallyfree of stabilizers such as ethylene diamine tetraacetic acid (EDTA) andsalts thereof, Dequest, and Desferal (e.g., as used in compositionsdescribed in U.S. Pat. Nos. 6,776,982 and 6,468,548); polymerscomprising chitosan (e.g., as used in compositions described in U.S.Patent Application No. 2003/0031718); linear polysaccharide compoundssuch as hyaluronic acid compounds (e.g., as used in compositionsdescribed in International Publication No. WO 02/100437); biocompatiblepolymers/thickeners such as polyoxyethylene-polyoxypropylene copolymers;antioxidants; and/or active agents other than ketotifen or naphazoline.For example, the methods herein disclosed may be useful for thestabilization of compositions consisting essentially of ketotifen or aketotifen salt and anti-redness agent, a nonionic tonicity agent, andwater, free or substantially free of these aforementioned components.

Alternatively, the methods herein disclosed are useful for thestabilization of an ophthalmic composition comprising ketotifen or aketotifen salt, naphazoline or naphazoline salt, a nonionic tonicityagent, and water, and a preservative, and optionally an acid, base orbuffer agent to adjust the pH of the composition.

The methods herein disclosed may be useful for the stabilization of anophthalmic composition consisting of ketotifen or a ketotifen salt,naphazoline or naphazoline salt, a nonionic tonicity agent, and waterfree or substantially free of buffer agents. The nonionic tonicity agentmay be present in a concentration such that the composition has anosmolality from 200 to 700 mOsm/kg, preferably from 400 to 600 mOsm/kg.The nonionic tonicity agent may be glycerol. The concentration ofglycerol may be about 2% to about 6%. The concentration of glycerolpreferably may be about 3% to about 5%, and most preferably, 4%.

The methods herein disclosed may be useful for the stabilization of anophthalmic composition of ketotifen or a ketotifen salt such that nomore than about 10% of the ketotifen or the ketotifen salt is degradedat 40° C. and 20% RH for at least 10 days. The methods herein disclosedalso may be useful for the stabilization of an ophthalmic composition ofnaphazoline or naphazoline salt such that no more than about 5% of thenaphazoline or the naphazoline salt is degraded at 40° C. and 20% RH forat least 10 days. Further, the methods herein disclosed may be usefulfor the stabilization of an ophthalmic composition of ketotifen andnaphazoline (or their salts) such that no more than about 10% of theketotifen or the ketotifen salt and no more than about 5% of thenaphazoline or the naphazoline salt when combined together are degradedat 40° C. and 20% relative humidity for at least 10 days.

EXAMPLES

The following examples are illustrative of the embodiments of thepresent invention and are not to be interpreted as limiting orrestrictive. Notwithstanding that the numerical ranges and parameterssetting forth the broad scope of the invention are approximations, thenumerical values set forth in the specific examples are reported asprecisely as possible. Any numerical value, however, inherently containscertain uncertainties, as expressed by the standard deviation found inits respective measurements (e.g., pH), where such standard deviationcan be determined or estimated. By way of example, a pH value is to beregarded as to be within a range of ±0.2.

In one example, a method of stabilizing an ophthalmic composition isprovided as follows. The method comprises preparing a solutioncomprising ketotifen fumarate in a concentration of from about 0.01% toabout 0.05%, naphazoline hydrochloride in a concentration of from about0.01% to about 0.1%, a glycerol concentration such that the solution hasan osmolality of from 200 to 700 mOsm/kg (milliosmole/kg) and water. Apreservative may be added. The concentration of preservative may beabout 0.01%, however, lower or higher concentrations may be used, inappropriate cases. The preservative can be benzalkonium chloride. Thesolution is prepared by contacting the salts with the water.

In another example, a method of preparing a stabilized ophthalmiccomposition is provided as follows. The method comprises preparing acomposition consisting essentially of ketotifen fumarate in aconcentration of from about 0.01% to about 0.05%, naphazolinehydrochloride in a concentration of from about 0.01% to about 0.1%, aglycerol concentration such that the composition has an osmolality offrom 200 to 700 mOsm/kg, benzalkonium chloride in a concentration ofabout 0.01%, a buffering agent; and water. The method further comprisesadjusting a pH value of the composition to less than about 5. Byadjusting the pH of the ophthalmic composition the pH value ismaintainable between about 4.3 and about 4.8 at 40° C. and 20% RH for atleast 10 days.

In still another example, a method of stabilizing an ophthalmiccomposition is provided. The method comprises preparing a compositioncomprising a ketotifen base in a concentration of about 0.025%, anaphazoline base in a concentration of about 0.02% to about 0.05%,glycerol in a concentration of about 2% to 6%, and water. The pH valueof the composition is adjusted, where the pH value is maintainablebetween about 4.3 and about 4.8 at 40° C. and 20% RH for at least 10days. The osmolality of the composition is from about 400 to about 600mOsm/kg. The composition may further comprise a citrate buffer in aconcentration of about 0.002M or less. The composition may furthercomprise benzalkonium chloride in a concentration of about 0.01%.

In yet another example, a method of stabilizing an ophthalmiccomposition is provided. The method comprises adjusting a pH value ofthe ophthalmic composition to less than about 5, the compositioncomprising a ketotifen or a ketotifen salt, an anti-redness agent, andwater, where the ketotifen or the ketotifen salt is degraded less than10% at 40° C. and 20% RH for at least 10 days. The ketotifen salt may beketotifen fumarate. The ketotifen fumarate may be present in aconcentration of from about 0.01% to about 0.05%. The anti-redness agentmay be a naphazoline salt, preferably naphazoline hydrochloride. Thenaphazoline hydrochloride may be present in a concentration of fromabout 0.01% to about 0.1%. In the above example, glycerol may bepresent, preferably in a concentration of about 2% to about 6%. Thecomposition may further comprise a citrate buffer in a concentration ofabout 0.002M or less provided that no more than about 10% of theketotifen degrades after at least 10 days at 40° C. and 20% RH. Thecomposition may further comprise benzalkonium chloride in aconcentration of about 0.005% to about 0.02%.

Formulations comprising ketotifen and naphazoline free or substantiallyfree of buffering agents were prepared with adjusted initial pH values.Controls comprising ketotifen and naphazoline with various bufferingagents were also prepared with adjusted initial pH ranges. Theformulations and the control samples were tested for their stability atvarious temperatures and RHs. The pH of the formulations and the controlsamples were tested using a Fisher Acumet pH meter. Degradation analysisof the active ingredients in the formulations was performed using HPLCusing control samples for ketotifen and naphazoline. The HPLC procedureutilized a Xterra 3.5 um C18, 150×2.1 mm ID, column (Waters, part#OOF-4114-DO) or equivalent. The gradient conditions consisted of mobilephase A comprising a 60:40 v/v mixture of a solution of 2 mLtriethylamine in 2000 mL water and a solution of 2 mL triethylamine inmethanol, respectively, and a mobile phase B comprising 2 mLtriethylamine in methanol. Mobile phase gradient conditions were assummarized in Table I. TABLE I Mobile Phase Gradient Conditions forKetotifen HPLC Assay Time Mobile Phase A Mobile Phase B (min) (% v/v) (%v/v) 0 100 0 10 100 0 20 50 50 35 50 50 36 100 0 45 0 0

Detection of the active ingredients was achieved with a variablewavelength ultraviolet detector. Degraded sample controls were preparedby pipetting 10 mL of the above solutions and combining with 0.1 mLsodium hydroxide solution (20 w/v %) followed by heating for 30 minutesat 70° C. After cooling, the pH was adjusted to 4.8±0.5 with dilute HClsolution.

Ketotifen fumarate concentration was calculated using equation (I):$\begin{matrix}{{{mg}\text{/}{mL}\quad{ketotifen}\quad{fumarate}} = {\frac{A_{Ketspl}}{A\quad{avg}_{Ketstd}} \times {Std}\quad{Diln} \times P_{std} \times M_{st}}} & (I)\end{matrix}$where A_(ketspl)=area of ketotifen in sample chromatogram;Aavg_(Ketstd)=average area of ketotifen from bracketed standards; StdDiln 32 standard dilutions; P_(std)=purity of standard expressed as adecimal; and M_(st)=Moisute factor (e.g., (100-limit of detection/100).

Naphazoline hydrochloride concentration was calculated using equation(II): $\begin{matrix}{{{mg}\text{/}{mL}\quad{naphazoline}\quad{hydrochloride}} = {\frac{A_{Naphspl}}{A\quad{avg}_{Naphstd}} \times {Std}\quad{Diln} \times P_{std}}} & ({II})\end{matrix}$where A_(Naphspl)=area of naphazoline in sample chromatogram;Aavg_(Naphstd)=average area of naphazoline from bracketed standards; StdDiln=standard dilutions; and P_(std)=purity of standard expressed as adecimal.

The data is summarized in Tables II-V. Table II depicts experimentalresults of storage at 55° C./20% RH for four weeks of buffered controlsample solutions A-F and unbuffered formulation G. The samples at pH 6.5and pH 6 (A, B, D and E) were dropped from the stability testing after 1week, since assay results indicated that ketotifen concentration haddropped to less than 15% of the initial ketotifen concentration. Thesebuffered samples (A, B, D and E), however, maintained their initial pHvalues for the 1 week. TABLE II Conc. of Buffering Agent Initial Final %Ketotifen % Naphazoline Sample Composition Buffer M pH pH detecteddetected A Ketotifen/Naphazoline citrate 0.02 6.5 ND <15 ND BKetotifen/Naphazoline citrate 0.02 6.0 ND <15 ND C Ketotifen/Naphazolinecitrate 0.02 5.5 5.5 60.0 ND D Ketotifen/Naphazoline phosphate 0.02 6.5ND <15 ND E Ketotifen/Naphazoline phosphate 0.02 6.0 ND <15 ND FKetotifen/Naphazoline phosphate 0.02 5.5 5.5 60.0 ND GKetotifen/Naphazoline None 0 5.5 4.5 85.0 86.0Stability Study Conditions: 55° C./20% RH, 4 weeksND = not determined

Table II indicates that the initial pH value of the buffered solutions Cand F remained at their initial pH values; however, ketotifen assayresults indicated that the ketotifen concentration had dropped to 60% ofthe initial ketotifen concentration. In contrast, for the unbufferedformulation sample G, which decreased in initial pH value after about 1week, ketotifen assay results indicated that the ketotifen concentrationhad dropped to only 85% of the initial ketotifen concentration.Naphazoline assay results for the unbuffered formulation sample Gindicated that the naphazoline concentration had dropped to 86% of theinitial naphazoline concentration. Thus, the unbuffered formulationsample G maintained a higher ketotifen and naphazoline concentrationwith a decrease in initial pH of 5.5 to a pH value of 4.5 compared tothe buffered controls. The data of Table II indicates that there islittle distinguishable difference between the type of buffer used(citrate or phosphate) and the extent of degradation of active agentobserved. TABLE III Conc. of Buffering Agent Initial Final % Ketotifen %Naphazoline Sample Composition Buffer (M) pH pH detected detected HKetotifen/Naphazoline citrate 0.005 5.5 5.5 66.0 79.0 IKetotifen/Naphazoline citrate 0.005 5.0 5.0 70.0 83.0 JKetotifen/Naphazoline phosphate 0.005 5.5 5.5 68.0 78.0 KKetotifen/Naphazoline phosphate 0.005 5.0 5.0 73.0 81.0 LKetotifen/Naphazoline None 0 5.5 4.5 79.0 NDStability Study Conditions: 55° C./20% RH 4 weeksND = not determined

Table III depicts experimental data directed to stabilizingketotifen/naphazoline solutions formulated without buffer versuscontrols having reduced concentration of buffer. Thus, four bufferedcontrol samples (H-K) and an unbuffered formulation (L) were stabilitytested at 55° C./20% RH. The controls contained reduced levels of buffer(25% less than the previous controls) and initial pH values of 5.5 and5. The unbuffered formulation L was adjusted to an initial pH value of5.5.

The data of Table III indicates that all of the buffered controlsmaintained their respective pH values throughout the stability study.Unbuffered formulation L decreased in pH value from an initial pH valueof 5.5 to a value of 4.5. Assay results of % initial ketotifen andnaphazoline concentrations of the post-stability tested compositionsshowed that the greatest amount of degradation occurred in the bufferedsamples. No significant difference in degradation of active ingredientswas observed between citrate and phosphate buffer at the pH valuestested. Decreasing either the citrate or phosphate buffer concentrationreduced the total degradation of ketotifen.

Naphazoline assay recoveries for the lower concentration phosphate andcitrate buffered controls were marginally improved over control sampleswith higher concentration of buffer when of the initial pH value wasadjusted lower. TABLE IV Conc. of Buffering Agent Initial Final %Ketotifen % Naphazoline Sample Composition Buffer (M) pH pH detecteddetected M Ketotifen/Naphazoline citrate 0.002 4.8 4.7 72.0 99.0 NKetotifen/Naphazoline citrate 0.001 4.8 4.5 77.0 96.0 OKetotifen/Naphazoline phosphate 0.004 4.8 4.7 71.0 99.0 PKetotifen/Naphazoline phosphate 0.002 4.8 4.5 65.0 98.0 QKetotifen/Naphazoline + 2.2% Glycerol None 0 4.8 4.5 92.0 99.7 RKetotifen/Naphazoline + 4% Glycerol None 0 4.8 4.4 92.0 99.7 SKetotifen + 2.2% Glycerol None 0 4.8 4.4 ND ND T Ketotifen/NaphazolineNone 0 4.5 4.0 97.4 102.7 U Ketotifen/Naphazoline None 0 4.0 3.7 98.099.9Stability Study Conditions: 55° C./20% RH, 4 weeksND = not determined

Table IV depicts additional buffered controls M-P with lowerconcentrations of buffer and unbuffered formulations Q-U. The bufferconcentrations were chosen so as to find a break point concentrationwhere the concentration of buffer would not be able to maintain theinitial pH value over time. The buffered controls M-P and unbufferedformulations Q-U were adjusted to have initial pH values of 4.8.

As indicated in Table IV, at 55° C., the pH values for the bufferedcontrols M-P decreased from their initial value over the four weeks. Thedata indicate that the greatest decrease of initial pH value for thebuffered control samples was observed for control sample O (0.001Mcitrate; final pH value 4.5) and control sample P (0.002M phosphate;final pH value 4.5), which indicated that these concentrationsrepresented the break point concentration for the respective bufferingagents for the ketotifen/naphazoline formulation. At 0.002M citrate and0.004M phosphate, concentrations exceeding the break pointconcentration, the data indicated that these formulations experiencedlevels of ketotifen degradation of greater than 25% or more. Otherbuffer systems besides citrate buffer and phosphate buffer are envisagedas providing pH stability and solution stability to active agentophthalmic formulations such as ketotifen and ketotifen/naphazolineformulations provided that the break point of the particular buffersolution is determined and not exceeded.

Table IV also contains stability data obtained from unbuffered ketotifenand unbuffered ketotifen-naphazoline solutions comprising nonionictonicity agents. Solutions of unbuffered ketotifen-naphazoline with 2.2%glycerin (sample Q), unbuffered ketotifen-naphazoline 4% glycerin(sample R) and unbuffered ketotifen with 2.2% glycerin (sample S) wereprepared with adjusted low pH values and tested as described above.These formulations exhibited decreased pH over time as previouslyobserved and maintained greater than 90% initial ketotifenconcentration.

Two additional unbuffered formulations were prepared and tested asdescribed above. Thus, samples T and U were formulated with adjustedinitial pH values of 4.5 and 4.0, respectively, and their stabilitytested at 55° C. for 4 weeks. TABLE V Conc. of Buffering Agent InitialFinal % Ketotifen % Naphazoline Sample Composition Buffer (M) pH pHdetected detected V Ketotifen/Naphazoline citrate 0.002 4.8 4.8 93.1*100* W Ketotifen/Naphazoline citrate 0.001 4.8 4.6 95.1* 100* XKetotifen/Naphazoline phosphate 0.004 4.8 4.7 87*  99.6* YKetotifen/Naphazoline phosphate 0.002 4.8 4.7 87*  99.2* AAKetotifen/Naphazoline + 2.2% Glycerol None 0 4.8 4.3 96.5 101.1 BBKetotifen/Naphazoline + 4% Glycerol None 0 4.8 4.4 97.0 101.5Stability Study Conditions: 40° C./ 20% RH for 1 week*Determined after one month

As shown in Table V, the initial pH values of the unbufferedformulations AA and BB decreased while the initial concentrations ofactive agents did not decrease significantly. In contrast, the bufferedcontrols maintained their pH values, but the initial concentrations ofactive agents decreased significantly.

For the unbuffered nonionic tonicity added formulations Q, R, AA and BBthe pH values decreased after stability testing from their initiallyadjusted pH values. The results found in Tables IV and V indicate thatunbuffered solutions containing nonionic tonicity agents, such asglycerol, as in samples Q, R, AA and BB, will also maintain ketotifenand/or naphazoline stability during testing or storage as compared tothe buffered controls.

Although, the degradation of ketotifen and naphazoline were reduced oreliminated, the decrease in initial pH values for samples T and U tovalues of 4.0 and 3.7, respectively, were observed. At these pH valuesare not be recommended, as the comfort of more sensitive users may beimpaired.

As shown in Tables II-V, the results of stability testing of theunbuffered formulations, with or without nonionic tonicity agentindicate lower initial pH values of solutions comprising active agents,as in the method herein described, provide a better stability profilefor ophthalmic solutions. This applies to ophthalmic solutionscomprising a plurality of active agents, e.g., ketotifen/naphazoline.Therefore, the methods herein described provide for greater efficacy andlonger shelf life of ocular drug products.

While the buffered formulations tested in the foregoing experimentsprovided the formulations with a stable pH, they yielded fasterdegradation of the ketotifen and/or naphazoline. However, thedegradation of ketotifen and/or naphazoline could be reduced to aboutless than ten percent after one month at 40° C. and 50° C., even in thepresence of 0.002 M or less citrate buffer or 0.004 M or less phosphatebuffer with the present invention. The data presented hereindemonstrates that by adjusting the pH value of a ketotifenfumarate/naphazoline hydrochloride solution longer shelf life and asignificantly reduced degradation of ketotifen and/or naphazolineactives are provided. Based on the data described above, it is envisagedthat the improvement in stability for the ketotifen/naphazoline solutioncan be extrapolated to methods where an initial pH value is adjusted toa range of about 4.5 to about 5.

Representative samples of the various formulations described above weretested for ocular comfort. Typically, the testing studies involveplacing a drop of one formulation in one eye and a drop of a secondformulation in the other eye of the subject. Subjects evaluated ocularcomfort immediately after each drop and two minutes later. The subjectsindicated ocular comfort as acceptable or not acceptable. The subjectswere unaware as to the identity of the formulations.

Buffered and unbuffered formulations as described above were tested forocular comfort. Unbuffered formulations were preferred over bufferedformulations with regard to ocular comfort as determined by testsubjects. Phosphate buffered formulations were preferred over citratebuffered formulations in the pH range of 5.6 to 5.8 with regard toocular comfort as determined by test subjects.

In subsequent studies of ocular comfort with solutions having pH valuesof 4 to 4.8, it was observed that unbuffered solutions with these pHvalues were also acceptable with regard to ocular comfort as determinedby test subjects. Extrapolation of this trend in ocular comfort and thenature of the buffer system to pH values of 4.8 to 5 are thereforeenvisaged, e.g., unbuffered>phosphate>citrate buffer below the breakpoint concentration. Thus, within a range of initial pH values of 4 to5, both the stability of the actives and the ocular comfort ofophthalmic solutions may be maximized using the methods hereindescribed. The pH value of the ophthalmic composition may be furtheradjusted as needed or desired after storage, sterilization, etc., orprior to use.

In one aspect, the present invention provides a pharmaceuticalcomposition that comprises ketotifen or a ketotifen salt, which ispresent at a concentration from about 0.001% to about 0.2% (w/v) (oralternatively, from about 0.001 to about 0.1% (w/v), or from about 0.005to about 0.1% (w/v), or from about 0.05 to about 0.05% (w/v)), wherein apH of the composition remains at less than 5 at 40° C. and 20% RH for atleast 10 days. In certain other embodiment, the pH of the compositionremains in a range from about 4.3 to about 5 (or alternatively, fromabout 4.3 to about 4.8) at 40° C. and 20% RH for at least 10 days.

In certain other embodiments, a pharmaceutical composition consistsessentially of: (a) ketotifen or a ketotifen salt, which is present at aconcentration from about 0.001% to about 0.2% (w/v) (or alternatively,from about 0.001 to about 0.1% (w/v), or from about 0.005 to about 0.1%(w/v), or from about 0.05 to about 0.05% (w/v)); (b) naphazoline or anaphazoline, which is present at a concentration from about 0.001% toabout 0.2% (w/v) (or alternatively, from about 0.001 to about 0.1%(w/v), or from about 0.005 to about 0.1% (w/v), or from about 0.05 toabout 0.05% (w/v)); and (c) a pharmaceutically acceptable carrier;wherein a pH of the composition remains at less than 5 at 40° C. and 20%RH for at least 10 days.

In still certain other embodiment, a pharmaceutical composition consistsessentially of: (a) ketotifen or a ketotifen salt, which is present at aconcentration from about 0.001% to about 0.2% (w/v) (or alternatively,from about 0.001 to about 0.1% (w/v), or from about 0.005 to about 0.1%(w/v), or from about 0.05 to about 0.05% (w/v)); (b) naphazoline or anaphazoline, which is present at a concentration from about 0.001% toabout 0.2% (w/v) (or alternatively, from about 0.001 to about 0.1%(w/v), or from about 0.005 to about 0.1% (w/v), or from about 0.05 toabout 0.05% (w/v)); (c) a tonicity-adjusting agent; and (d) apharmaceutically acceptable carrier; wherein a pH of the compositionremains at less than 5 at 40° C. and 20% RH for at least 10 days. Incertain aspects, the tonicity-adjusting agent is present at aconcentration such that the osmolality of the composition is in therange from about 200 to about 700 mOsm/kg (or alternatively, from about220 to about 600 mOsm/kg, or from about 250 to about 400 mOsm/kg).

In still certain other embodiments, at least 90% of each of saidketotifen, ketotifen salt, naphazoline, and naphazoline salt, whenpresent, remains in the composition after storage at 40° C. and 20% RHfor at least 10 days.

In further embodiments, the composition is an aqueous solution, anoil-in-water emulsion, a dispersion, a gel, or a gelable formulation.

In still further embodiments, the composition has a viscosity in a rangefrom about 5 to about 10,000 mPa·s (or centipoises). Alternatively, theviscosity is in a range from about 5 to about 1,000 mPa·s.

A composition of the present invention can be used to treat, ameliorate,or reduce a condition resulting from allergy. For example, a compositionof the present invention can be applied topically to treat, ameliorate,or reduce the severity of, allergic conjunctivitis or symptoms thereof,such as pink eye, itchy eye, or combinations thereof. A composition ofthe present invention may be applied to the ocular surface in the formof eye drops, in one or more drops once per day, twice per day, or threetimes or more per day.

In another embodiment, a composition of the present invention can beformulated to be used topically for dermatological applications totreat, ameliorate, or reduce allergic symptoms.

As used herein, “comprising,” “including,” “containing,” “characterizedby,” and grammatical equivalents thereof are inclusive or open-endedterms that do not exclude additional, unrecited elements or methodsteps. “Comprising” is to be interpreted as including the morerestrictive terms “consisting of” and “consisting essentially of.” Asused herein, “consisting of” and grammatical equivalents thereof excludeany element, step, or ingredient not specified in the claim.

As used herein, “consisting essentially of” and grammatical equivalentsthereof limit the scope of a claim to the specified materials or stepsand those that do not materially affect the basic and novelcharacteristic or characteristics of the claimed invention.

While the invention has been described in detail and with reference tospecific embodiments thereof, it will be apparent to one skilled in theart that various changes and modifications can be made without departingfrom the spirit and scope of the invention.

1. A method of preparing a stabilized ophthalmic composition, the methodcomprising: (a) preparing an aqueous solution consisting essentially of:(1) ketotifen or a ketotifen salt in a concentration from about 0.001%to about 0.2% (w/v); (2) naphazoline or a naphazoline salt in aconcentration from about 0.001% to about 0.2% (w/v); (3) glycerol; (4) apreservative; and (5) water; and (b) adjusting a pH value of the aqueoussolution to less than or equal to about 5; thereby providing saidstabilized ophthalmic composition, wherein the pH value of theophthalmic composition is maintainable between about 4.3 to about 4.8when kept at 40° C. and 20% relative humidity for at least 10 days. 2.The method of claim 1, wherein said ketotifen or ketotifen salt is in aconcentration from about 0.01% to about 0.05% (w/v), and saidnaphazoline or naphazoline salt is in a concentration from about 0.01%to about 0.1% (w/v).
 3. The method of claim 2, wherein said adjusting apH comprises adding an adjusting agent that consists essentially of asolution of fumaric acid and sodium fumarate, or a solution of dilutehydrochloric acid.
 4. The method of claim 2, wherein the glycerol ispresent at a concentration such that the solution has an osmolality offrom 200 to 700 mOsm/kg.
 5. The method of claim 2, wherein the glycerolis present at a concentration such that the solution has an osmolalityof from 400 to 600 mOsm/kg.
 6. The method of claim 2, wherein glycerolis present at a concentration from about 1% to about 6% (w/v).
 7. Themethod of claim 2, wherein no more than about 10% of the ketotifen orthe ketotifen salt is degraded at 40° C. and 20% relative humidity forat least 10 days.
 8. The method of claim 2, wherein no more than about5% of the naphazoline or the naphazoline salt is degraded at 40° C. and20% relative humidity for at least 10 days.
 9. The method of claim 2,wherein less than 10% of the ketotifen or the ketotifen salt and lessthan 5% of the naphazoline or the naphazoline salt are degraded at 40°C. and 20% relative humidity for at least 10 days.
 10. A method ofpreparing a stabilized ophthalmic composition, the method comprising:(a) preparing an aqueous solution consisting essentially of: (1)ketotifen or a ketotifen salt in a concentration of from about 0.001% toabout 0.2% (w/v); (2) naphazoline or a naphazoline salt in aconcentration of from about 0.001% to about 0.2% (w/v); (3) glycerol;(4) benzalkonium chloride; (5) water; and (6) a buffering agent; and (b)adjusting a pH value of the aqueous solution to less than or equal toabout 5; thereby providing a stabilized ophthalmic composition whereinthe pH value of the ophthalmic composition is maintainable between about4.3 to about 4.8 when kept at 40° C. and 20% relative humidity for atleast 10 days.
 11. The method of claim 10, wherein said ketotifen orketotifen salt is in a concentration from about 0.01% to about 0.05%(w/v); and said naphazoline or a naphazoline salt is in a concentrationof from about 0.01% to about 0.1% (w/v).
 12. The method of claim 11,wherein the buffering agent is present in a concentration such that aninitial pH value of the aqueous solution decreases when kept at 40° C.and 20% relative humidity for at least 10 days.
 13. The method of claim11, wherein the buffering agent is citrate that is present in aconcentration of about 0.002M or less; or phosphate that is present at aconcentration of 0.004M or less.
 14. A method of preparing a stabilizedophthalmic composition, the method comprising: (a) preparing aophthalmic composition comprising: (1) ketotifen in a concentration ofabout 0.001% to about 0.2% (w/v); (2) naphazoline in a concentration ofabout 0.001% to about 0.2% (w/v); (3) glycerol in a concentration ofabout 2% to 6% (w/v); and (4) water; and (b) adjusting the pH value ofthe ophthalmic composition; thereby providing said stabilized ophthalmiccomposition such that the pH value of the ophthalmic composition isbetween about 4.3 and about 4.8 at 40° C. and 20% relative humidity forat least 10 days.
 15. The method of claim 14, wherein the osmolality ofthe composition is from about 400 to about 600 mOsm/kg.
 16. The methodof claim 15, wherein the composition further comprises a citrate bufferat a concentration of about 0.002M, or less or a phosphate buffer at aconcentration of 0.004M or less.
 17. A method of preparing a stabilizedaqueous ketotifen salt composition, the method comprising: admixing anaqueous ketotifen salt composition with a pH adjusting agent, the pHadjusting agent providing a pH of the aqueous ketotifen salt compositionin a range from about 4.8 to less than 5, wherein the composition isessentially free of buffer agents; and allowing the pH of the aqueousketotifen salt composition to adjust to between 4.3 to less than 4.8;thereby providing a stabilized aqueous ketotifen salt such that no morethan about 10% of the ketotifen salt is degraded at 40° C. and 20%relative humidity for at least 10 days.
 18. The method of claim 17,wherein the pH adjusting agent consists essentially of dilutehydrochloric acid.
 19. The method of claim 18, wherein the pH adjustingagent consists essentially of a mixture of fumaric acid and sodiumfumarate.
 20. The method of claim 17, wherein the ketotifen salt isketotifen fumarate.
 21. The method of claim 20, wherein the ketotifenfumarate is present in a concentration of from about 0.01% to about0.05%.
 22. The method of claim 19, further comprising an anti-rednessagent.
 23. The method of claim 22, wherein the anti-redness agent isnaphazoline or naphazoline hydrochloride.
 24. The method of claim 23,wherein the naphazoline or naphazoline hydrochloride is present in aconcentration of from about 0.01% to about 0.1%.
 25. The method of claim17, further comprising a nonionic tonicity agent.
 26. The method ofclaim 25, wherein the nonionic tonicity agent is present at aconcentration such that the composition has an osmolality of from 200 to700 mOsm/kg.
 27. The method of claim 25, wherein the nonionic tonicityagent is present at a concentration such that the composition has anosmolality of from 400 to 600 mOsm/kg.
 28. The method of claim 25,wherein the nonionic tonicity agent is glycerol.
 29. The method of claim28, wherein the glycerol is present in a concentration of about 2% toabout 6%.
 30. A pharmaceutical composition comprising: (a) ketotifen ora ketotifen salt, which is present at a concentration from about 0.001%to about 0.2% (w/v); and (b) naphazoline or a naphazoline salt, which ispresent at a concentration from about 0.001% to about 0.2% (w/v);wherein a pH of the composition remains at less than 5, when stored at40° C. and 20% RH for at least 10 days.
 31. The pharmaceuticalcomposition of claim 30, wherein the concentration is in a range fromabout 0.001% to about 0.1% (w/v).
 32. The pharmaceutical composition ofclaim 30, wherein the pH of the composition remains in a range fromabout 4.3 to about 5, when stored at 40° C. and 20% RH for at least 10days.
 33. A pharmaceutical composition consisting essentially of: (a)ketotifen or a ketotifen salt, which is present at a concentration fromabout 0.001% to about 0.2% (w/v); (b) naphazoline or a naphazoline salt,which is present at a concentration from about 0.001% to about 0.2%(w/v); and (c) a pharmaceutically acceptable carrier; wherein a pH ofthe composition remains at less than 5 at 40° C. and 20% RH for at least10 days.
 34. The pharmaceutical composition of claim 33, wherein theconcentration is in a range from about 0.001% to about 0.1% (w/v).
 35. Apharmaceutical composition consisting essentially of: (a) ketotifen or aketotifen salt, which is present at a concentration from about 0.001% toabout 0.2% (w/v); (b) naphazoline or a naphazoline salt, which ispresent at a concentration from about 0.001% to about 0.2% (w/v); (c) atonicity-adjusting agent; and (d) a pharmaceutically acceptable carrier;wherein a pH of the composition remains at less than 5 at 40° C. and 20%RH for at least 10 days.
 36. The pharmaceutical composition of claim 35,wherein the concentration is in a range from about 0.001% to about 0.1%(w/v).
 37. The pharmaceutical composition of claim 36, wherein thetonicity-adjusting agent is present at a concentration such that theosmolality of the composition is in the range from about 200 to about700 mOsm/kg.
 38. The pharmaceutical composition of claim 37, wherein atleast 90% of each of said ketotifen, ketotifen salt, naphazoline, andnaphazoline salt, when present, remains in the composition after storageat 40° C. and 20% RH for at least 10 days.
 39. The pharmaceuticalcomposition of claim 38, wherein the composition is an aqueous solution,an oil-in-water emulsion, a dispersion, a gel, or a gelable formulation.40. The pharmaceutical composition of claim 38, wherein the compositionhas a viscosity in a range from about 5 to about 10,000 mPa·s.